Jan Trna

Expression of COX-2 is associated with accumulation of p53 in pancreatic cancer: analysis of COX-2 and p53 expression in premalignant and malignant ductal pancreatic lesions.

Objectives Cyclooxygenase-2 (COX-2) and tumor suppressor p53 are molecules that are linked to the oncogenesis of pancreatic cancer. COX-2 represents a key modulatory molecule in inflammation and carcinogenesis, and is known to be implicated in the positive regulation of growth and tumorigenesis. Abnormal expression of p53 is common in many human neoplasms including pancreatic cancer. Recent studies demonstrated functional interactions between p53 and COX-2. The p53-dependent upregulation of COX-2 was proposed to be another mechanism by which p53 could abate its own growth-inhibitory and apoptotic effects. Methods In this study, we immunohistochemically analyzed the expression of COX-2 and p53 in 95 pancreatic resection specimens [adenocarcinomas, 95 lesions; pancreatic intraepithelial neoplasias (PanINs), 155; normal ducts, 70]. Results The expression of COX-2 increased progressively with the grade of ductal lesions (P<0.00001). A statistically significant difference of COX-2 expression between normal ducts and low-grade PanINs was revealed (P=0.0042). COX-2 overexpression was demonstrated in 82 PanINs (52.9%), and in 76 adenocarcinomas (80%). No significant correlation between the grade of adenocarcinoma and COX-2 expression was revealed (P=0.2). The expression of p53 again increased progressively with the grade of lesions (P<0.00001) with a significant increase in high-grade PanINs. A correlation between COX-2 and p53 expression levels in carcinomas was revealed (P=0.0002), and an accumulation of p53 was associated with COX-2 overexpression in premalignant and malignant ductal lesions. Conclusion These findings confirmed the generally accepted pancreatic cancer progression model, and supported the concept of the interactive role of COX-2 and p53 in pancreatic cancer carcinogenesis, which offers opportunities for targeted therapy and chemoprevention of pancreatic cancer using COX-2 inhibitors.

The Role of Chronic Inflammation: Chronic Pancreatitis as a Risk Factor of Pancreatic Cancer

Pancreatic carcinoma is a condition with late diagnosis and one for which there is no effective screening method. One possible diagnostic approach of so-called early adenocarcinoma is the identification and systematic examination of individuals at risk for this condition. Between 1992 and 2005 we systematically observed 223 individuals diagnosed with chronic pancreatitis. In this 14-year period we performed classical biochemical tests, endoscopic ultrasound, CT scans and ERCP. We also asked about the number of cigarettes smoked per year and classified individuals consuming regularly more than 80 g of alcohol per day for 5 years for men and 50 g of alcohol per day for 5 years for women as having the alcoholic form of chronic pancreatitis. The remaining patients were classified according to the TIGARO classification. Alcohol-related etiology was detected in 73.1% of patients, 21.5% had the chronic obstructive form and only 5.4% were classified as idiopathic pancreatitis. Pancreatic carcinoma was detected in 13 patients with chronic pancreatitis (5.8%), 3 patients were diagnosed with gastric carcinoma and 1 with esophageal carcinoma. Pancreatic malignancy developed mainly in patients with the alcoholic form of pancreatitis (4.5%). In the 14-year period 11 subjects died, out of which 8 cases were related to pancreatic carcinoma. Pancreatic and extrapancreatic cancer localized in the gastrointestinal tract are serious complications of chronic nonhereditary pancreatitis. Systematic observation of patients with chronic pancreatitis must be performed with the aim of early diagnosis of pancreatic malignancies (but also including other types).

Lack of significant liver enzyme elevation and gallstones and/or sludge on ultrasound on day 1 of acute pancreatitis is associated with recurrence after cholecystectomy: A population-based study

BACKGROUND In a population-based study, we examined recurrence rates of acute pancreatitis (AP) after cholecystectomy performed to prevent recurrences of AP. METHODS We abstracted data from medical records of all Olmsted county residents who underwent cholecystectomy at Mayo Clinic for the management of presumed gallstone or idiopathic AP between 1990 and 2005 (n = 239). Based on (i) significantly elevated liver enzymes (≥threefold increase of alanine aminotransferase or aspartate aminotransferase) on day 1 and (ii) the presence of gallstones/sludge in the gall bladder, we categorized patients into 4 groups: A (i + ii), B (i but not ii), C (ii but not i), and D (neither i nor ii). Recurrence rates of AP after cholecystectomy were determined in all groups. RESULTS The median follow-up after cholecystectomy was 99 months (range, 8-220). AP recurred in 13 of 142 patients (9%) in group A, 1 of 17 patients (6%) in group B, 13 of 57 patients (23%) in group C, and 14 of 23 patients (61%) in group D (P < .0001 D vs. all other groups and P = .001 C vs. groups A and B). No difference was seen in recurrence rates in groups A vs. B (P = 1.0). Recurrences were more frequent in patients with normal liver enzymes (A + B vs. C + D; P = .000003) and in patients without sonographic evidence of gallstones/sludge (A + C vs. B + D; P = .0008). CONCLUSION When AP is associated with significantly elevated liver enzymes on day 1, recurrence rates after cholecystectomy are low (9%). However, postcholecystectomy recurrence rates of AP are high in those without such laboratory abnormalities (34%), especially in those without gall bladder stones/sludge (61%) on abdominal ultrasonography. Our results raise doubts about the efficacy of cholecystectomy to prevent recurrent AP in patients with the absence of either a significant elevation of liver tests on day 1 of AP or gallstones and/or sludge in the gall bladder on initial ultrasound examination.

Immunoglobulin G4-Related Cholangitis: A Variant of IgG4-Related Systemic Disease

IgG4-related sclerosing cholangitis as part of IgG4 systemic-related diseases is commonly associated with autoimmune pancreatitis. Major clinical manifestations of IgG4-related sclerosing diseases are apparent in the organs in which tissue fibrosis with obstructive phlebitis is pathologically induced. IgG4-related sclerosing cholangitis is included within the heterogeneous group of ‘sclerosing cholangitis’. Sclerosing cholangitis may be associated with choledocholithiasis, infection or biliary malignancies. Sclerosing cholangitis of unknown etiology is called primary sclerosing cholangitis (PSC). Conservative therapy of PSC is usually unsuccessful, the disease involves extra- and/or intrahepatic biliary tree, and the end point of this disease is liver cirrhosis. Typically, PSC is identified at the age of 30 to 40 years, and the disease is frequently associated with inflammatory bowel diseases. On the other hand, IgG4-related sclerosing cholangitis is not associated with inflammatory bowel diseases. In patients with IgG4-related sclerosing cholangitis, a first symptom can be obstructive jaundice, whereas obstructive jaundice is rarely present in PSC. Clinically, patients with IgG4-related sclerosing cholangitis are older at diagnosis compared to patients with PSC. A typical diagnostic feature of IgG4-related sclerosing cholangitis is elevation of serum immunoglobulin G4. In patients with IgG4-related sclerosing cholangitis, response to steroid therapy is high; in patients with PSC corticosteroid therapy is unsuccessful. Histochemically abundant infiltration of IgG4-positive plasma cells is detected in the biliary duct wall. Histologically, we can identify dense lymphoplasmacytic infiltration of the bile duct wall, transmural fibrosis, lymphoplasmacytic infiltration and fibrosis in the periportal area of the liver – a typically obliterative phlebitis. The biliary epithelium is usually intact in contrast to PSC, where mucosal erosion is often present. Steroids are the first-choice therapy of IgG4-related sclerosing cholangitis. In the literature, cholangiocarcinoma in patients with IgG4- related sclerosing cholangitis was not described, whereas cholangiocarcinoma develops in up to 10–30% of patients with PSC.

Diabetes Mellitus in Pancreatic Cancer Patients in the Czech Republic: Sex Differences

Aims. The prevalence of diabetes mellitus in pancreatic cancer patients and control subjects was compared. Methods. Retrospective evaluation of 182 pancreatic cancer patients and 135 controls. The presence of diabetes was evaluated and the time period between the diagnosis of diabetes and pancreatic cancer was assessed. A subanalysis based on patient sex was conducted. Results. Diabetes mellitus was present in 64 patients (35.2%) in pancreatic cancer group and in 27 patients (20.0%) in control group (χ 2 = 8.709; P = 0.003). In 18 patients (28.1% of diabetic pancreatic cancer patients) diabetes was new-onset. Diabetes was new-onset in 23.3% of females compared to 38.1% of males (χ 2 = 1.537; P = 0.215). The overall prevalence of diabetes was significantly higher among female pancreatic cancer patients (25% versus 43.9%; χ 2 = 7.070, P = 0.008), while diabetes prevalence was equally represented in the control group patients (22.1% versus 17.2%; χ 2 = 0.484, P = 0.487). Conclusion. The prevalence of diabetes mellitus in study group of pancreatic cancer patients was significantly higher when compared to control group. Pancreatic cancer patients with diabetes were predominantly females, while diabetes was equally prevalent among sexes in the control group. Therefore, patient sex may play important role in the risk stratification.

Unusual Multiorgan Immunoglobulin G4 (IgG4) Inflammation: Autoimmune Pancreatitis, Mikulicz Syndrome, and IgG4 Mastitis

Autoimmune pancreatitis (AIP) type 1 is commonly associated with simultaneous involvement of extrapancreatic organs. Sclerosing cholangitis, sialadenitis, retroperitoneal fibrosis, Sjögren syndrome, and other extrapancreatic lesions are often observed concurrently with AIP. High levels of immunoglobulin G4 (IgG4) in the blood serum and affected tissues are typical of this diagnostic entity. We describe a case report of a 58-year-old female with findings of AIP (according to Asian criteria), IgG4-positive mastitis, and histologically verified Mikulicz syndrome. The effect of corticoid therapy supported the diagnosis of AIP and simultaneously led to the eradication of recurrent mastitis. To the best of our knowledge, this is the first reported case of concurrent findings of AIP and IgG4 mastitis. Our case report supports the concept of systemic IgG4 syndrome with multisystem involvement. Timely diagnosis and appropriate therapy can be effective in a high percentage of patients.

Usefulness of exercise tissue doppler echocardiography for prognostic stratification of congestive heart failure patients with left ventricular systolic dysfunction.

AIM Determination of the importance of exercise tissue Doppler echocardiography in prognostic stratification of congestive heart failure patients with systolic dysfunction. METHODS 106 patients with congestive heart failure and LVEF ≤ 45% on optimal pharmacotherapy were included in the study. Results of resting and post-exercise echocardiography, cardiopulmonary exercise test and serum BNP levels were available for all patients. Two patient groups were constituted, based on the prognostic classification. Group I contained 21 patients with poor prognosis (defined by predicted value of pVO2 < 76% together with both VE/VCO2 slope > 32.7 and BNP > 210 pg/mL) and group II with 85 patients who did not meet the criteria. RESULTS The patient groups significantly differed in indexed volume of left atrium, mitral regurgitation severity, rest and post-exercise systolic velocity of mitral annulus and in rest and post-exercise E/Em. Multivariate analysis identified E/Em as the only independent predictor of prognosis. E/Em at rest (post-exercise) ≥ 16.6 (≥ 18.7) defined poor prognosis with sensitivity of 71% (86%) and specificity of 71% (71%). CONCLUSION Our study suggests usefulness of exercise tissue Doppler echocardiography for prognostic stratification of patients with congestive heart failure with possible superiority to resting parameters.

The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies with increasing incidence. The poor prognosis is due to the aggressive nature of the tumor, late detection, and the resistance to chemotherapy and radiotherapy. A radical surgery procedure is the only treatment that has been shown to improve the 5-year survival rate to 20-25%. However, the majority of patients (80-85%) are diagnosed with locally advanced or metastatic disease and just 15-20% patients are diagnosed in an early stage allowing them to undergo the potentially curative surgical resection. The early detection of PDAC without the use of invasive methods is challenging and discovery of a cost-effective biomarker with high specificity and sensitivity could significantly improve the treatment and survival in these patients. In this review, we summarize current and newly examined biomarkers in early PDAC detection.

T1294 Normal Liver Enzymes On Day #1 of Acute Pancreatitis Predict High Recurrence Rates of Pancreatitis After Cholecystectomy

G A A b st ra ct s percutaneous tube study in 12, by ERCP in 1, and by colonoscopy and contrast enema in 1 patient. Antecedent percutaneous catheter drains were present in 13 patients (92.9%). Fistulization was to the splenic flexure in 6, left colon in 5, and right colon in 3. Median time from the diagnosis of SAP to the discovery of PCF was 66.5 days. Treatments included percutaneous catheter drainage and antibiotics in all 14, endoscopically-placed transpapillary pancreatic duct stents in 9, and endoscopically-placed internal stents through the stomach in 2. Two patients (14.3%) underwent surgery. One patient died 4 months after resolution of a PCF and 1 month after last follow up. Conclusion: To our knowledge, this is the largest reported case series of PCF at a single institution in the English literature. PCF is an uncommon, often late complication of SAP. Not infrequently, it is found incidentally during radiographic studies. PCFs generally resolve with non-operative management including antibiotics, percutaneous drainage, and/or endoscopic internal stenting and heal without adverse consequence and rarely need surgical intervention.